Abstract/Summary As a functionally important aspect of cognitive flexibility, reversal learning leads to inhibition/suppression of previously established memory. Effective reversal learning is fundamental for information updating and essential for adaptation to changing environmental cues. Regarding its impact on mental health, deficits in cognitive flexibility and reversal learning are prevalent in psychological and mood disorders, and are considered as an emerging therapeutic target. However, there is limited understanding of mechanisms underlying cognitive flexibility. Our recent study found that, contrary to the previously recognized role of cAMP signaling in regulating broad spectrum of learning and memory, type 8 adenylyl cyclase (Adcy8) specifically regulates the activity- dependent suppression of old memory following reversal learning. With our recently developed Adcy8 conditional knockout mice, we will determine the effects of region- and cell type-specific ADCY8 deficiency on synaptic and cognitive flexibility: reversal/suppression of the previously established synaptic potentiation (i.e. depotentiation) and reversal/suppression of the previously established memory. Further, computational analysis with transcriptome landscape predicts that the PI3K (phosphatidylinositide 3-kinase)/Akt (protein kinase B)-GSK3? (glycogen synthase kinase 3?) signaling cascade is the molecular substrate of ADCY8. We will determine whether restoration of the ADCY8-PI3K/Akt-GSK3? signaling cascade causally corrects the defective synaptic depotentiation and reversal/suppression of old memory. Finally, we will determine whether restoration of the ADCY8-PI3K/Akt-GSK3? signaling cascade normalizes genomic landscape, which associates with neuronal function and may represent holistic molecular phenotype. Considering that there are 10 different ADCYs in mammalian system, the outcome of this project will delineate a unique of role of ADCY8 in regulating a specific domain of cAMP signaling that is functionally linked to cognitive and synaptic flexibility. We also expect that the mechanisms learned from this study may suggest targeted therapeutic strategies to attenuate reversal learning deficits in certain patient population with altered cAMP-PI3K/Akt-GSK3? signaling.